WO1990009172A1 - Inhibiteurs de renine contenant du phosphore - Google Patents

Inhibiteurs de renine contenant du phosphore Download PDF

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Publication number
WO1990009172A1
WO1990009172A1 PCT/US1989/000636 US8900636W WO9009172A1 WO 1990009172 A1 WO1990009172 A1 WO 1990009172A1 US 8900636 W US8900636 W US 8900636W WO 9009172 A1 WO9009172 A1 WO 9009172A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
compound
nmr
mhz
alkyl
Prior art date
Application number
PCT/US1989/000636
Other languages
English (en)
Inventor
Ronald T. Wester
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to US07/741,442 priority Critical patent/US5468732A/en
Priority to PCT/US1989/000636 priority patent/WO1990009172A1/fr
Priority to EP90301297A priority patent/EP0385593A1/fr
Priority to PT93144A priority patent/PT93144A/pt
Priority to CA002009982A priority patent/CA2009982A1/fr
Priority to JP2035074A priority patent/JPH0694477B2/ja
Publication of WO1990009172A1 publication Critical patent/WO1990009172A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the proteolytic enzyme renin which has a molecular weight of about 40,000, is produced in and secreted into the blood by the kidney. It is known, to be active in vivo in cleaving the naturally-occurring plasma glycoprotein angiotensinogen, in the case of human angiotensinogen at the bond between the leucine (10th) and valine (11th) amino acid residues at the N-terminal end of the angiotensinogen:
  • the circuiting N-terminal decapeptide (angiotensin I) formed by the above cleaving action of renin is subsequently broken down by the body to an octapeptide known as angiotensin II.
  • Antiotensin II is known to be a potent pressor substance, i.e., a substance that is capable of inducing a significant increase in blood pressure, and is believed to act by causing the constriction of blood vessels and the release of the sodium-retaining hormone aldosterone from the adrenal gland.
  • the renin-angiotensinogen system has been implicated as a causative factor in certain forms of hypertension and congestive heart failure.
  • One means of alleviating the adverse effects of the functioning of the renin-angiotensinogen system is the administration of a substance capable of inhibiting the angiotensinogen-cleaving action of renin.
  • a substance capable of inhibiting the angiotensinogen-cleaving action of renin A number of such substances are known, including antirenin antibodies, pepstatin and naturally-occurring phospholipid compounds.
  • R 3 is methylthiomethyl and R 4 is methoxy and R 5 is isopropoxy, where R 4 and R 5 together are butylene and where R 4 and R 5 together are propylenedioxy.
  • R 3 is methylthiomethyl and R 4 and R 5 are each methoxy, where R 4 and R 5 together are propylenedioxy and where R 4 and R 5 together are pentylene.
  • the present invention also includes a method for treating hypertension in a mammal which comprises administering to said mammal an antihypertensive effective amount of the compounds of the present invention and a pharmaceutical composition comprised of the compounds of the present invention in unit dosage form and a carrier.
  • the present invention embraces pharmaceutically acceptable salts of the biologically active compounds. Such salts are those which are non-toxic at the dosages administered. Since compounds of the invention may contain both basic and acidic groups, both acid addition and alkali addition salts are possible.
  • Pharmaceutically acceptable acid addition salts include e.g., the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, maleate, mesylate, fumarate, citrate, acid citrate, tartrate, bitartrate, succinate, gluconate and saccharate salts.
  • Pharmaceutically acceptable alkali addition salts include e.g., the sodium, potassium, calcium and magnesium salts.
  • the compounds of this invention exhibit antihypertensive activity in vivo in mammals, including humans. At least a substantial portion of this activity results from their ability to inhibit the cleavage of angiotensinogen by renin. Although we do not wish to be limited by the following theory of mechanism, it is likely that the mechanism of the renin-inhibiting activity of the compounds of the invention is their selective binding (as compared to angiotensinogen) to renin.
  • the compounds of the invention exhibit an enzyme-inhibiting activity that is selective for renin as against other beneficial enzymes such as cathepsin D. Because of their low molecular weights they exhibit favorable solubility characteristics in aqueous media, thus making oral administration feasible, and can be synthesized at a commercially realistic cost.
  • the compounds of the present invention are also useful against congestive heart failure.
  • the compounds of the invention can be prepared by methods familiar to those skilled in the art.
  • the basic sub-unit of the preferred chemical synthesis is the acylation of the unprotected alpha-amino group of an amino acid residue with an amino acid having an activated (for acylation purposes) carboxylie function and a suitable protecting group bonded to its own alpha-nitrogen to form a peptide bond between the two amino acid residues, followed by the removal of said protecting group.
  • This synthesis sub-unit of couplingdeblocking is performed repeatedly to build up the polypeptide, starting from the C-terminal end of the molecular structure and working to the N-terminal end.
  • a preformed dipeptide portion can be coupled with a single amino acid using the polypeptide coupling techniques or the preformed tripeptide can be acylated with R 1 using known acylation methods.
  • the amino acids utilized to synthesize the compounds of the present invention are commercially available (as free acids, salts or esters, etc.) in both alpha-amino protected and alpha-amino unprotected forms.
  • the amides or esters when subjected to hydrogen chloride in dioxane, lose the t-butoxycarbonyl protecting group from the amino moiety. Acylation of the resulting amino esters or amides are carried out using 1-hydroxybenzotriazole and a carbodiimide. Removal of the blocking group on imidazole with acetic acid-water gives the final product.
  • the activity of the compounds of the present invention as inhibitors of the angiotensinogen-cleaving activity of renin can be determined by studying (1) their ability to inhibit the angiotensinogen-cleaving activity of renin in vitro and (2) their ability to antagonize the exogenous renin-induced pressor response in vivo.
  • the compounds of the present invention can be administered as antihypertensive agents by either the oral or parenteral routes of administration, with the former being preferred for reasons of patient convenience and comfort.
  • these antihypertensive compounds are normally administered orally in dosages ranging from about 0.5 mg to about 50 mg per kg of body weight per day and 0.1 mg to about 5 mg per kg of body weight per day when given parenterally; variations will necessarily occur depending upon the condition of the subject being treated and the particular compound being administered.
  • treatment is commenced at a low daily dosage and increased by the physician only if necessary.
  • these compounds may be administered in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages.
  • novel compounds of the invention can be orally administered in a wide variety of different dosage forms, i.e., they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes.
  • the compounds of this invention are present in such oral dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, in amounts which are sufficient to provide the desired unit dosages,
  • tablets for purposes of oral administration, tablets
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules;
  • preferred materials in this connection would also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • Example 11A The product of Example 11A (1.2 g) was treated with 4N hydrogen chloride in dioxane at room temperature for 2 hours to afford 1.1 g of the desired product.
  • Boc phenylalanine (1.14 g) was coupled with 1.0 g of the product of Example 11B using the DEC procedure of Example 1D.
  • the crude product was chromatographed (methanol-methylene chloride, 1:19, v:v) to afford 1.04 g of pure material.
  • Example 1D The crude material was chromatographed (methanol-methylene chloride, 1:9, v:v) to give 79 mg of product as a mixture of hydroxyl epimers.
  • Example 19A The product of Example 19A (159 mg) was deprotected using hydrogen chloride according to the procedure of Example IB to give 79 mg of the product.
  • Morpholinocarbonyl-Phe (61 mg) was coupled with 74 mg of Ser-HACPP (OCH 3 ) 2 ⁇ HCl using the DEC procedure of Example 1D to afford, after chromatographing
  • the titled compound was prepared according to the procedure of Example 19, substituting BocHis for BocSer.
  • Example 21B The product of Example 21B (251 mg) was coupled with 200 mg of the product of Example 11B using the DEC procedure of Example 1D.
  • the crude product was chromatographed (methanol-methylene chloride, 1:19, v:v) to afford 147 mg of the desired material as a 3:1 mixture of hydroxyl epimers.
  • Example 33D The product of Example 33D (100 mg) was coupled with 125 mg of the product of Example 11B using the DEC procedure of Example 1D.
  • the crude product was chromatographed (methanol-methylene chloride, 1:19, v:v) to give 86 mg of product as a mixture of hydroxy epimers.
  • Example 33 The procedure of Example 33 was employed using the appropriate amine in place of 3-hydroxypyrrolidine to give the following products:
  • Morpholinocarbonyl-PheSMeCys-HACPP (O-nC 3 H 7 ) 2
  • the titled compound was prepared using the procedure of Example 19, substituting Boc-SMeCys for Boc-Ser and di-n-propylphosphite for dimethylphosphite.
  • the titled compound was prepared by the procedures of Examples 21/48 by substituting morpholine for
  • Example 37 To the product of Example 37 (50 mg) in 15 ml of chloroform was added 33 mg of m-chloroperbenzoic acid at 0o C. After stirring for 1 hour, the mixture was diluted with 50 ml of ethyl acetate and washed with a 10% sodium sulfite solution (2 ⁇ 50 ml) and a 0.1N sodium hydroxide solution. The organic phase was dried over magnesium sulfate, concentrated and chromatographed (methanol-methylene chloride, 8:92, v:v) to give 18 mg of the desired sulfone.
  • Example 37 The product of Example 37 (50 mg) in 5 ml of chloroform at 0o C. was treated with 16 mg of m-chloroperbenzoic acid and the mixture allowed to stir for 1 hour. Solid sodium sulfite (200 mg) was added, the mixture concentrated and the residue chromatographed (methanol-methylene chloride, 8:92, v:v) to give 32 mg of a 1:1 mixture of sulfoxides.
  • Example 54A The product of Example 54A (230 mg) was deprotected with hydrogen chloride in dioxane as in Example 1 to give 230 mg of crude product.
  • Example 54B An aqueous work-up gave 245 mg of product as a 3 : 1 mixture of hydroxyl epimers.
  • Example 54C The product of Example 54C (230 mg) was deprotected using hydrogen chloride in dioxane as in Example 1 to give 240 mg of crude product.
  • Example 54D 230 mg of the product of Example 54D using the standard DEC procedure of Example 1D to give, after chromatographing (methanol-methylene chloride, 7.5:92.5, v:v), 102 mg of the desired product.
  • Example 62B 255 mg was coupled with 381 mg of morpholinocarbonyl-PheSMeCys using the general procedure of Example 1F to give, after
  • the titled compound was prepared by substituting Boc-Nle for Boc-SMeCys in Example 37.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

On décrit des polypeptides contenant du phosphore agissant comme inhibiteurs de rénine, utiles au traitement de l'hypertension.
PCT/US1989/000636 1989-02-16 1989-02-16 Inhibiteurs de renine contenant du phosphore WO1990009172A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US07/741,442 US5468732A (en) 1989-02-16 1989-02-16 Phosphorus containing renin inhibitors
PCT/US1989/000636 WO1990009172A1 (fr) 1989-02-16 1989-02-16 Inhibiteurs de renine contenant du phosphore
EP90301297A EP0385593A1 (fr) 1989-02-16 1990-02-07 Inhibiteurs de la rénine contenant du phosphore
PT93144A PT93144A (pt) 1989-02-16 1990-02-14 Processo para a preparacao de polipeptideos que contem fosforo uteis como inibidores da renina
CA002009982A CA2009982A1 (fr) 1989-02-16 1990-02-14 Inhibiteurs de la renine contenant du phosphore
JP2035074A JPH0694477B2 (ja) 1989-02-16 1990-02-15 燐含有レニン阻害剤

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1989/000636 WO1990009172A1 (fr) 1989-02-16 1989-02-16 Inhibiteurs de renine contenant du phosphore

Publications (1)

Publication Number Publication Date
WO1990009172A1 true WO1990009172A1 (fr) 1990-08-23

Family

ID=22214842

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1989/000636 WO1990009172A1 (fr) 1989-02-16 1989-02-16 Inhibiteurs de renine contenant du phosphore

Country Status (5)

Country Link
EP (1) EP0385593A1 (fr)
JP (1) JPH0694477B2 (fr)
CA (1) CA2009982A1 (fr)
PT (1) PT93144A (fr)
WO (1) WO1990009172A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5217958A (en) * 1988-03-03 1993-06-08 E. R. Squibb & Sons, Inc. 1,2-hydroxy phosphonates and derivatives thereof
US5662885A (en) * 1994-07-22 1997-09-02 Resolution Pharmaceuticals Inc. Peptide derived radionuclide chelators

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007117560A2 (fr) * 2006-04-05 2007-10-18 Vitae Pharmaceuticals, Inc. Pipéridine et morpholine inhibiteurs de la rénine

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4016148A (en) * 1975-01-27 1977-04-05 Hoffmann-La Roche Inc. Peptide derivatives of phosphonic and phosphinic acids and intermediates therefor
US4128542A (en) * 1976-07-13 1978-12-05 Hoffmann-La Roche Inc. Peptide derivatives
US4143134A (en) * 1976-07-21 1979-03-06 Hoffmann-La Roche Inc. Halo-phosphonopeptides
US4250085A (en) * 1977-12-23 1981-02-10 Hoffmann-La Roche Inc. Acyl derivatives
US4416833A (en) * 1981-05-04 1983-11-22 E. R. Squibb & Sons, Inc. Substituted carbonyl phosphinyl-alkanoyl compounds
US4416831A (en) * 1981-04-27 1983-11-22 E. R. Squibb & Sons, Inc. Amino and substituted amino phosphinylalkanoyl compounds
US4432971A (en) * 1981-08-03 1984-02-21 E. R. Squibb & Sons, Inc. Phosphonamidate compounds
US4455506A (en) * 1981-05-11 1984-06-19 Gte Products Corporation Contrast enhanced electroluminescent device
US4560680A (en) * 1982-03-15 1985-12-24 E. R. Squibb & Sons, Inc. Aminoalkyl and related substituted phosphinic acid angiotensin converting enzyme inhibitors
US4716155A (en) * 1981-12-24 1987-12-29 E. R. Squibb & Sons, Inc. Phosphorus containing compounds and hypotensive use thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY103189A (en) * 1986-10-31 1993-05-29 Pfizer Nor-statine and nor-cyclostatine polypeptides
DE3825242A1 (de) * 1987-07-27 1989-02-09 Ciba Geigy Ag Durch schwefelhaltige gruppen substituierte histidinylamino-verbindungen
HUT52785A (en) * 1988-03-03 1990-08-28 Squibb & Sons Inc Process for producing 1,2-hydroxy-phosphonates and derivatives

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4016148A (en) * 1975-01-27 1977-04-05 Hoffmann-La Roche Inc. Peptide derivatives of phosphonic and phosphinic acids and intermediates therefor
US4128542A (en) * 1976-07-13 1978-12-05 Hoffmann-La Roche Inc. Peptide derivatives
US4143134A (en) * 1976-07-21 1979-03-06 Hoffmann-La Roche Inc. Halo-phosphonopeptides
US4250085A (en) * 1977-12-23 1981-02-10 Hoffmann-La Roche Inc. Acyl derivatives
US4416831A (en) * 1981-04-27 1983-11-22 E. R. Squibb & Sons, Inc. Amino and substituted amino phosphinylalkanoyl compounds
US4416833A (en) * 1981-05-04 1983-11-22 E. R. Squibb & Sons, Inc. Substituted carbonyl phosphinyl-alkanoyl compounds
US4455506A (en) * 1981-05-11 1984-06-19 Gte Products Corporation Contrast enhanced electroluminescent device
US4432971A (en) * 1981-08-03 1984-02-21 E. R. Squibb & Sons, Inc. Phosphonamidate compounds
US4716155A (en) * 1981-12-24 1987-12-29 E. R. Squibb & Sons, Inc. Phosphorus containing compounds and hypotensive use thereof
US4560680A (en) * 1982-03-15 1985-12-24 E. R. Squibb & Sons, Inc. Aminoalkyl and related substituted phosphinic acid angiotensin converting enzyme inhibitors

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5217958A (en) * 1988-03-03 1993-06-08 E. R. Squibb & Sons, Inc. 1,2-hydroxy phosphonates and derivatives thereof
US5662885A (en) * 1994-07-22 1997-09-02 Resolution Pharmaceuticals Inc. Peptide derived radionuclide chelators

Also Published As

Publication number Publication date
JPH0694477B2 (ja) 1994-11-24
EP0385593A1 (fr) 1990-09-05
CA2009982A1 (fr) 1990-08-16
PT93144A (pt) 1990-08-31
JPH03163094A (ja) 1991-07-15

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